Functionalized Grignard Reagents and Their Applications in ...evans.rc.fas.harvard.edu/pdf/smnr_2005_Sapountzis_Ioanns.pdf · Functionalized Grignard Reagents and Their Applications

Functionalized Grignard Reagents and Their Applications

in New Amination Reactions

Evans Group Seminar November 9, 2004

Preparation of Functionalized Organomagnesium Reagents throughHalogen-Magnesium Exchange

iPrMgBrI MgBr

THF -40 °C to 0 °C

FG FG

MgBr

EtO2C

MgBr

EtO2C N NMe2

MgBr

NC (i-Pr)2NOC

MgBr MgBr

Br

OEtO2C MgBr

N

NC

MgBrN

MgBr

I

Ts

MgBr

CO2Et

NCMgClEtO2C

O O

O PhMgCl

recent review:P. Knochel et al. Angew. Chem. Int. Ed. 2003, 42, 4302.

Nitrofunctionalized Grignard Reagents

NO2R-MgX

I

NO2 NO2E+

ClMg E

NNu–O

O

- 1,2-, 1,4- and 1,6-addition or O-attack possible- Single-electron tranfer (SET)

and radical-anion coupling

New Amination Reactions using Arylmagnesium Reagents

NO2

I R-MgXN

OO

MgClNO2

EE+

NO2

INO2

Li E+

NO2

EPhLi (1.05 equiv.)

-100 °C, 3 minTHF:ether:pentane

4:1:1 16 - 69 %

C. E. Tucker, T. N. Majid and P.Knochel, J. Am. Chem. Soc., 1992, ,114, 3983.J. F. Cameron and J. M. Fréchet, J. Am. Chem. Soc.,1991, 113, 4303.

Nitro-Substituted Arylmagnesium Reagents

NO2I

FG

NO2MgCl

(CuCN·2LiCl)

E+

NO2E

up to 95 %

PhMgCl(1.05 equiv.)

-40 °C, 5 minTHF

(- PhI)FG: CO2Et, CN, I, NO2, OMe, H, Me, COPh, CONR2

FGFG

NO2

CN

OH

Ph

NO2 OH

Ph

O

Ph

NO2

CO2Et

Me

Me

NO2

94 %93 % 76 % 76 %

NO2 OH

Ph

EtO2C

NO2

MeO

NO2 OH

c-Hex

O2N

NO2

Ph

I

O

95 % 76 % 74 % 77 %

I. Sapountzis, P. Knochel Angew. Chem. 2002, 114, 1680; Angew. Chem. Int. Ed. 2002, 41, 1610.

Nitro-Substituted Heteroarylmagnesium Reagents

N

NO2

I -78 °C, 2 h

N

IO2N

NO2

N MgCl

-40 °C, 2 hN

O2NMgCl

N

NO2

OH

Ph

PhMgCl(1.05 equiv)

-78 °C, 5 minTHF(-PhI)

N

O2N

OHPhPhMgCl

(1.05 equiv)

-40 °C, 5 minTHF(-PhI)

PhCHO

PhCHO

55 %

78 %

N NH2

NO2

N I

NO2NaNO2; CuI

DMSO, HI50 °C, 30 min

63 %

m- and p-Nitro-Substituted Arylmagnesium Reagents

NO2

I

NO2

I

PhMgCl

PhMgCl

ClMg

NO2

MgCl

NO2

– 78 °C

– 78 °C

Nitro-Substituted Arylmagnesium Reagents

FGI

FGMgCl

O2N O2N

FGEPhMgCl E+

(CuCN·2LiCl)O2N

THF, -78 °C5 min

EtO2C

Ph

O

O2NO2N

OPh Et2NOC

O2N

Ph

O

54 - 94 %FG = CO2Et; CONR2; COPh; N=N-NR2; OTs; Boc2N

NO2

OTs

PhI

OH

NN

O2N

N

NO2

NBoc2

Ph

O

O2N

OMe

NO2

IOH

Ph

Me

61%58% 78%71%

94% 68%54% 78%

Nitro-Substituted Arylmagnesium Reagents in Negishi-cross coupling Reactions

EtO2C

INO2

EtO2C

ZnXNO2

EtO2C

NO21.) PhMgCl -40 °C, 10 min (-PhI)

2.) ZnBr2 -40 °C, 10 min

Pd(dba)2 (5 mol%)tfp (10 mol%)

-40 °C - rt, 2 h

78 %

EtO2C

NO2NO2NO2

NC

OMe

O2N

NO2CO2Et

68 %75 % 85 % O2N

NO2NO2

55 %

FG

NO2

I

MgBr

Me

Me

Me

NO2

ZnX

FG FG

NO2

Ar

1.)

-40 °C, 20 min

2.) ZnBr2 -40 °C, 10 min

ArI (1. 5 equiv)

Pd(dba)2 (5 mol%)tfp (10 mol%),-20 °C - rt, 3 h 55-85 %FG: CO2Et, CN, NO2, CO2NR2

m- and p-Nitro-Substituted Arylmagnesium Reagents in Negishi cross-coupling reactions

O2N

I

OOCO2Et

ZnX

O2N

INC

OTsNO2

NO2

OTsCN

NO2

O2N

CO2EtCN

1.) PhMgCl -78 °C, 10 min

2.) ZnBr2 -78 °C, 10 min

(2 equiv.)

Pd(dba)2 (5 mol%)tfp (10 mol%),-78 °C - rt, 5 h 83 %

I. Sapountzis, H. Dube, P. Knochel Adv. Synth. Catal. 2004, 346, 709.

73 % 77 %

A failed reaction?

NO2

I

NO2

I

PhMgCl

PhMgCl

ClMg

NO2

MgCl

NO2

– 78 °C

– 78 °C

NOMgCl

I

NOMgCl

I

Early Studies on Reactions between Nitroarenes and Organomagnesium Reagents

DDQ

NO2RMgX

NR

H

OMgXO N

H R

OMgXO

NH2R

NO2R

NO2

R

NH2

R

+

reduction

R= alkyl

NO2 MgX NXMgOO

reduction

NHO

G. Bartoli Acc. Chem. Res. 1984, 17, 109.Highlight: A. Ricci, M. Fochi Angew. Chem. Int. Ed. 2003, 42, 1444

The Bartoli Indole Synthesis

NO2R

MgX

MgXN OXMgO

R

OMgX

NOMgX

HR

C2H4

NXMg O

R

NOMgXXMg

RH3O+N

XMg O

HR

NHR

MgXNO

R

G. Bartoli, G. Palmieri, M. Bosco, R. Dalpozzo Tetrahedron Lett. 1989, 30, 2129.

Reducing the Hydroxylamine – Access to Diarylamines

One-Pot-Procedure desirable

Reduction conditions:Pd/C-NaBH4; Raney-Ni;Fe/AcOH; BEt3 in THF; SnCl2 in HCl;SnCl2 in EtOH; SmI2 in THF; various Lewis acids andNaBH4 in different solventsFeCl2 in THF + NaBH4

NO2

Br

MgCl

CO2Et

N

BrEtO2C

OH

HN

BrEtO2C

–20°CTHF, 1 h

+

New Amination Reaction using Aryl-Magnesium Reagents and Nitrobenzenes

ONAr2

O

Ar2 NOMgCl

OAr1

Ar2 NO

Ar1MgCl

Ar1MgCl

Ar1

NHAr2

Ar2 NAr1

OMgCl

1) Ar1MgCl (2 equiv.), THF, -20 °C2) FeCl2/NaBH4, -20 °C, 2 h

- Ar1OMgCl

FeCl2/NaBH4 -20 °C, 2 h

slow

fast

O2N

HNI

FG2

FG1 68-95 %( 2.3 equiv )

1) i-PrMgCl -20 °C, 0.5 h

2)

-20 °C, 2 h3) FeCl2/NaBH4, rt, 2 h

FG2FG1

FG: CO2Et, CN, I, NO2, OMe, H, F, Br, CF3, SMe, CONR2

New Amination Reactions using Arylmagnesium Reagents and Nitrobenzenes

EtO2C

HN

OTf

Br

HNNC

CO2Et

HN

F

HN

OMe

78 %

79 %

85 %

97 %

MeO

HN

SMe

MeO

HN CN

HN OMe

EtO2C

HN

Br73 %

79 %

72 %

92 %

I

HN

NMe2

HN

MeO

CF3

HN

HN Ph

HN

OMe

85 %

67 %

75%

94 %

I. Sapountzis, P. Knochel J. Am. Chem. Soc. 2002, 124, 9390

New Amination Reactions of Nitro-Heterocycles using Arylmagnesium Reagents

I

EtO2C O2N

N

S N

SHN

EtO2C( 2.3 equiv )

1) i-PrMgCl -20 °C, 0.5 h

2)

-20 °C, 2 h3) FeCl2/NaBH4, rt, 2 h

77 %

N

HN

EtO2C N

SHN

I

HN

N

PhN

HN

I

HN

NTos

N

HN

NN

75 %59 % 64 %

88 % 85 %44 %

Amination of Solid Phase Supported Nitrobenzenes using Arylmagnesium Reagents

O

ONO2

HO

OHN

HO

OHN

OMe

HO

OHN

Me

Me Me

HN

Ar

O

HO

92 % purityquant.

91 % purityquant.

98 % purityquant.

1. Ar-MgX (10 equiv) (THF, -20 °C, 2 h)

2. EtOH (0.5 mL)3. FeCl2 (5 equiv)4. NaBH4 (2.5 equiv) (rt, 2 h)5. TFA/CH2Cl2/H2O= 9:1:1

O

O O

HO

1.) iPrMgCl (10 Äq.) THF, –20 °C, 2 h

2.) THF, 2x 5 mL3.) PhNO24.) EtOH (0.5 mL)5.) FeCl2 (5 Äq.) NaBH4 (2.5 Äq.) RT, 2 h6.) TFA/CH2Cl2/H2O= 9:1:1

I OH

95% purity quant.

New Amination Reactions using Arylmagnesium Reagents and Nitrobenzenes

ClMg

NO2

FG

-20 °C, 2 h

2) FeCl2, NaBH4 -20 °C, 2 h

1)

2.3 equiv of ArMgXor

4.6 equiv of ArMgX

HN

HN

HN

NO2

FG

O2N

FG

FG

HN

HN

CN

44%

HN

HN

EtO2C CO2Et

HN NO2

HN

NO2

72 % 67 % 63 %

HN NO2

MeO68 %

HN

HN

95%I. Sapountzis, P. Knochel Synlett 2004, 955

New Amination Reactions using Arylmagnesium Reagents and Amino- or Hydroxy-Substituted Nitrobenzenes

OH

O2Nn

N

NO2

BocHN NBocHN

O2N

BocHN

O2N

O

NH

RO2NS

NNHBoc

O2N

R

Possible scaffolds that were of interest for Aventis:

Addition of various aromatic Grignard reagents:

N

HN

BocHN

Ph

73%

HN

Ph

88%

O

NHR

HN

CN

Ph

68%HO

Reduction and Amination saves one step for most of these substrates

Application in Removal of p-Nitrobenzyl Protecting Group

ClMg

NO2-20 °C, 2 h

2) FeCl2, NaBH4 -20 °C, 2 h3) CF3COOH 0.02 M in DCM 0 °C, 1h

1)

OBr

OH

Br80 %

ClMg

NO2

NEt -20 °C, 2 h

2) FeCl2, NaBH4 -20 °C, 2 h3) CF3COOH 0.02 M in DCM 0 °C, 1h

1)

70 %

PMBEt

Ph

NHEt PMB

Et

Ph

with N. Gommermann

see also: O. J. Plante, S. L. Buchwald and P. H Seeberger J. Am. Chem. Soc. 2000, 122, 7148.

Limitations of Amination Reactions using Arylmagnesium Reagentsand Nitrobenzenes

MgCl

CO2Et

NO2HN

CO2Et

FG FG

MgCl

NO2

NO2HN

NO2

FG FG

MgCl

Me

Me

Me

NO2FG

NN

HN

Me

Me Me

FG

traces

main product

FG

FG

Only Arylmagnesium Reagents

2 equiv. of Grignard needed

New Amination Reactions

Ar1 Ar2HN

Ar1 NH2

Ar1 NH Ar2

Ar2 X

X+

+

a

Ar1 NH

b

Ar1 NO

O

Ar2 Met

MgXAr2

+

+

Problems:leaving groupelectron poor aromatics

Pd-catalyzed:Ligand and Base tuningside reactions

Electrophlic Amination Reactions

NCF3

CF3CF3

F3C

OTs

S N3

ON

O

OO

N

N3

Ts N3

K. Narasaka

B. M. Trost

Synthetic equivalents for NH2

Kabalka

J. P. Genet V. Snieckus

O

ON

Li

OTsMe

MeMe

Ph2PO

ONR2

G. Boche

E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947

New Amination Reactions

Ar1 Ar2HN

Ar1 NH2

Ar1 NH Ar2

Ar2 X

X+

+

a

Ar1 NH

b

Ar1 NO

O

Ar2 Met

MgXAr2

+

+

Problems:leaving groupelectron poor aromatics

Pd-catalyzed:Ligand and Base tuningside reactions

Ar1 NO

Ar1 NN SO2Tol

New Amination Reactions using Arylmagnesium Reagents and Aryl-p-Tolylazo Sulfones

Acid Base Approx. pKa

ArSO3H ArSO3- -6.5

Ar3NH+ Ar3N -5 F3CCOOH F3CCOO- -1.0 Ar2NH2

+ Ar2NH 1 ArNH3

+ ArNH2 3-5 ArNR2H+ ArNR2 3-5 HCOOH HCOO- 3.77 CH3COOH CH3COO- 4.76 NH4

+ NH3 9.24 R3NH+ R3N 10-11

R

Zn

Ar1N N

TsAr2

RNH

Ar2

Ar1

R = H, Me, allyl, benzyl, Tos, Ms, Ac

still difficult

H

Ar1

N NTs

Ar2R

H

Zn

NHAr2

Ar1

easy

(AcOH : TFA 5 : 1)

Ar1N N

SO2Tol

Ar1N N

TsAr2

MgXNH

Ar2

Ar1

Ar2MgX reductive

cleavagevery difficult

various reduction conditionseverything that is reported

in literature failed


Ar1 NH2 Ar1 N2TsNa

CH2Cl2, RT

NaNO2

HBF4, RT Ar1N N

TsBF4

> 80% yield

1) Ar2MgX (1.1 eq) -20°C, 1h

2) C3H7I, NMP 20 °C, 3 h3) solvent evaporation

N NTsAr1

Ar2Ar1N N

Ts Zn

AcOH:TFA5:1

Ar1HN Ar2

63-86%overall yield

I. Sapountzis, P. Knochel Angew. Chem. Int. Ed. 2004, 43, 897


HN

EtO2C Br

68 %

HN

EtO2C CN64 %

HN

EtO2C Br

83 %

HN

EtO2C

Br80 %

I

HN

EtO2C

63 %

HN

Me BrMe

Me

69 %

N

HN

CO2Et

Ph

CO2Et

71 %

Fe

HN

Br

58 %

Cl

HN

59 %

HN

OMeOTf

MeO

HN

CO2Et

HN CF3

MeOCF3

81 %92 %

62 %

Cl

ClMeO


1) –20 °C, 1h2) allyl iodide, NMP 20 °C, 3 h

solvent evaporation3) Zn, AcOH 75 °C, 10 min

1) –20 °C, 1h2) allyl iodide, NMP 50 °C, 24 h

solvent evaporation3) Zn, AcOH 75 °C, 15 min

MgBr

N2Ts

R

N2Ts

CO2Et

IZn Me

HN

EtO2C

Me

HN

R

R = CO2Et, Br R = CO2Et; 62%R = Br; 67%

55

62%

New Amination Reactions using Arylmagnesium Reagentsand Aryl-p-Tolylazo Sulfones

HN

CO2Et

TfONN

Ts

CO2Et

TfO

N

HN

OMeN

NN

Ts

OMe

microwave

ZnAcOH/TFA 5:1

5 bar, 1h

overall yield 85%

microwave

ZnAcOH/TFA 5:1

5 bar, 2 h

overall yield 60%

HN

FG

NHN

Ts

FG

Raney-Nickel/ H2 (1 atm)

EtOH/ r.t. 12 h- 48h

FG: CO2Et FG: OMe FG: H

FG: H, OMe, CO2Et 96%88%76%

Challenging substrates

N

N

OEtO2CMgX

N

NR

I

N

N

NH2

Br

SMgX

HNF3C

CF3

CO2Et

some kinds of heterocycles

very electron-poor systemse.g.:

NH2

NH2

XMg

N

SMgX

N

triarylamines are not possiblee.g.:

1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction

NO2

RO

I

SO

OOF3C Ar

O

O Ar

O

O Ar

O

OAr

O

NO2

RO

ClMg

Me OAr

PhMgCl

R=

I

OTf

O2N

PhMgCl

MgCl

OTf

O2N O2NTHF–78 °C–PhI

decomposition

New Amination UsingSelective Benzyne Formation via I/Mg Exchange Reaction

LGI

LGMgCl NAr2

MgX

ArN

Ar

MgX

?

NAr2

EE+

FG FG FG FG FG

OTfI

O OTfLi O

2.) nBuLi -78 °C

1.)

K. Suzuki Synlett 2000, 520.

Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction

OTsI

OTsMgCl

OTs OH

Ph

95 %

iPrMgCl

-78 °C

PhCHO

-78 °C

OTsI

OTsMgCl

OO

iPrMgCl

-78 °C2 h

-78°C to RT 78 %2 h

OTsI

OTsMgCl

OO

iPrMgCl

-78 °C30 min

-78°C to RTFG FG FG FG

FG: CO2Me, CN FG = CO2Me: 73 %, 15 h CN : 77 %, 24 h


ORI

CO2Me

ORMgCl

CO2Me CO2Me

OO

CO2Me

iPrMgCl

–78 °C –78 °C - RT

–78 °C

OR

CO2Me

OH

PhPhCHO

O2S

Cl

O2S

CF3

CF3

O2S

CH3

O2S

Cl

Cl

Me

Me

Me

O

OSO2MeSO2CF3SO2CH2CF3

R =


ArO2SOI

ArO2SOMgCl

ArO2SO OH

PhiPrMgCl

-78 °CFG FG FG

PhCHO

-78 °C

FG = CO2Me, CN, CF3, Hal, [ NO2 (PhMgCl)]

Ar= 4-Chlorphenyl

Ar= 4-Chlorphenyl

ArO2SO OH

Ph

F3C

ArO2SO OH

Ph

CO2Me

ArO2SO OH

Ph

CN

ArO2SO OH

PhI

CN

ArO2SO OH

Ph

91 % 93 %95 % 95 %68 %

ArO2SO OH

Ph

NO2

95 %


-78°C to RT

ArO2SOI i-PrMgCl

-78 °CFG

OArO2SO

MgCl

FG FG

FG = CO2Me, CN, CF3, Hal, NO2

Ar= 4-Chlorphenyl

FG

CO2Me

O

CN

O

NO2

OO

CO2MeO

89 %71% 78 %78 % 58 %

OTBSEtO

94 %

CO2Me

I

I. Sapountzis, W. Lin, M. Fischer, P. Knochel Angew. Chem. Int. Ed. 2004, 43, 4364.

New Amination Using Selective 1,2 Dehydrobenzene Formation via I/Mg Exchange Reaction

-78°C to RT

ArO2SOI

i-PrMgCl

-78 °C

NEt2

H

ArO2SOMgCl 1.) Et2NMgCl

2.) H+

75 %

-78°C to RT

ArO2SOI

i-PrMgCl

-78 °C

SPh

I

-78°C to RT

ArO2SOI i-PrMgCl

-78 °C

SCHO

Br

ArO2SOMgCl

ArO2SOMgCl

1.) PhSMgCl

2.) I2

81 %

1.) Br-PhSMgCl

2.) DMF

75 %W. Lin

Summary

• Functionalized Nitrophenylmagnesium Reagents

• Electrophilic Aminations using Nitrobenzenes or Arylazosulphones

•Preparation of Functionalized Benzynes via I/Mg Exchange

FGMgCl

O2N

NO2MgCl

FG

HN

FG2FG1

NO2

FG1 Ar1N N

Ts

NR

FG

R

FG

Acknowledgement

Prof. Dr. Paul Knochel

Ludwig-Maximilians UniversitätAventis Pharma Germany

Krystyna BeckerHenry Dube, Robert Lewis, Markus Tegel, Markus Fischer

and Christina Despotopoulou

Functionalized Grignard Reagents and Their Applications in ...evans.rc.fas.harvard.edu/pdf/smnr_2005_Sapountzis_Ioanns.pdf · Functionalized Grignard Reagents and Their Applications

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